The treatment of Human Immunodeficiency Virus (HIV) infection, which is causative to the acquired immunodeficiency syndrome (AIDS), remains a major medical challenge. HIV is able to evade immunological pressure, to adapt to a variety of cell types and growth conditions and to develop resistance against currently available drug therapies. The latter include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), HIV-protease inhibitors (PIs) and the more recent fusion inhibitors.
Each of these drugs can only transiently restrain viral replication if used alone.
Insufficient drug potency, non-compliance, restricted tissue penetration and drug-specific limitations within certain cell types are amongst the factors that account for the incomplete suppression of HIV. This led to the introduction of combination therapy of several anti-HIV agents having a different activity profile. Significant progress was made by the introduction of “HAART” (Highly Active Anti-Retroviral Therapy), which has resulted in a significant reduction of morbidity and mortality in HIV patient populations treated therewith. Current guidelines for antiretroviral therapy recommend such triple combination therapy regimen even for initial treatment. However, none of the currently available drug therapies is capable of completely eradicating in HIV and long-term treatment usually results in suppressing virus replication to a level where it no longer can cause the outbreak of the symptoms associated with AIDS.
Currently used anti-HIV drugs require frequent administration of relatively high doses. The number and/or volume of dosage forms that need to be administered is commonly referred to as the “pill burden”. A high pill burden is undesirable for many reasons, such as the patient having to spend more time taking each dose and the patient having to store and/or transport a large number or volume of pills. A high pill burden also increases the risk that a patient will not take his or her entire dose, thereby failing to comply with the prescribed dosage regimen. As well as reducing the effectiveness of the treatment for that patient, this may also lead to the disease-causing organism or virus becoming resistant to the pharmaceutical agent.
Individuals infected by HIV virus often are unaware of the fact that they carry the virus and therefore constitute a continuous risk of transferring the infection to others. Even in developed countries this is still the case but in particular is a threat in many of the less-developed countries, where people have no or limited access to medical care, including to HIV diagnostic tools. Therefore, prevention of HIV transmission is a crucial component in the battle against the spread of HIV. Prevention currently focuses on avoiding sexual transmission, in particular by promoting the use of condoms in populations at risk of being infected, the careful monitoring of blood samples for the presence of HIV and the avoiding of contact with blood of potentially infected subjects.
Despite these measures there is always an imminent risk for certain population groups to become infected with HIV. This in particular is the case for those providing medical care to infected patients such as physicians, nurses and dentists. Other population groups at risk for example are breast-fed infants where the mother is infected, especially in developing countries where alternatives for breast-feeding are less obvious.
Hence there is a need for further means that provide prevention against transmission of HIV. There is a particular need for effective prevention means that are easy to apply. Providing such prevention means is an object of the present invention.
It now has been found that intermittent administration of parenteral formulations of the NNRTI TMC278 at time intervals of one week or longer result in plasma levels that are sufficient to provide prevention against transmission of HIV. A reduced number of administrations are needed which is advantageous in terms of pill burden and drug compliance of the individual at risk of being infected.
TMC278 is an NNRTI that currently is in clinical development. This compound is a highly potent drug not only showing pronounced activity against wild type HIV, but also against many of its mutated variants. The compound TMC278, its pharmacological activity as well as a number of procedures for its preparation have been described in WO-03/16306. Various conventional pharmaceutical dosage forms, including tablets, capsules, drops, suppositories, oral solutions and injectable solutions are exemplified therein.